Prostatic compensation of the vitamin D axis in African American men.

BACKGROUND. African American (AA) men are disproportionately affected by both prostate cancer (PCa) and vitamin D deficiency compared with European American (EA) men. Vitamin D deficiency is linked to increased PCa aggressiveness and mortality. Therefore, it has been hypothesized that vitamin D deficiency may contribute to the PCa disparity between AA and EA men. METHODS. We studied a cross sectional group of 60 PCa patients (AA, n = 31; EA, n = 29) who underwent radical prostatectomy. Vitamin D metabolites 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured in the serum and tissue by uHPLC-MS-MS. Tissue was laser capture microdissected, and gene expression was quantified by microarray. DNA isolated from whole blood was genotyped for West African ancestry markers and vitamin D-related SNPs. RESULTS. Serum concentrations of 25(OH)D were lower in AAs, but concentrations of 1,25(OH)2D in the prostate tissue were higher compared with EAs. Expression of the vitamin D receptor was higher in prostate tissue from AAs. Expression of the extracellular receptor of vitamin D binding protein, LRP2, was positively associated with West African ancestry and inversely associated with tissue 25(OH)D concentrations in AAs. CONCLUSIONS. The relationships between vitamin D binding protein LRP2 and vitamin D metabolites suggest that the prohormone is actively transported into the prostate, followed by intraprostatic conversion to the active hormone, rather than passive diffusion. These findings support the presence of a compensatory response in prostate tissue to vitamin D deficiency in AAs and reveal a previously unknown complexity involving tissue distribution of vitamin D metabolites. FUNDING. Department of Defense Prostate Cancer Research Program Idea Award for Disparities Research PC121923 (LN and RK) and the NIH 1R01MD007105 (RK).

[1]  G. Hardiman,et al.  Systems analysis of the prostate transcriptome in African-American men compared with European-American men. , 2016, Pharmacogenomics.

[2]  E. Rodriguez-Boulan,et al.  The fast-recycling receptor Megalin defines the apical recycling pathway of epithelial cells , 2016, Nature Communications.

[3]  Richard D. Smith,et al.  Free 25-Hydroxyvitamin D: Impact of Vitamin D Binding Protein Assays on Racial-Genotypic Associations , 2016, The Journal of clinical endocrinology and metabolism.

[4]  Richard D. Smith,et al.  Role of Assay Type in Determining Free 25-Hydroxyvitamin D Levels in Diverse Populations. , 2016, The New England journal of medicine.

[5]  R. Kittles,et al.  Vitamin D and Immune Response: Implications for Prostate Cancer in African Americans , 2016, Front. Immunol..

[6]  L. Nonn,et al.  Laser-capture Microdissection of Human Prostatic Epithelium for RNA Analysis. , 2015, Journal of visualized experiments : JoVE.

[7]  P. Kraft,et al.  Circulating vitamin D, vitamin D–related genetic variation, and risk of fatal prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium , 2015, Cancer.

[8]  L. Arab,et al.  Association between Plasma 25-Hydroxyvitamin D, Ancestry and Aggressive Prostate Cancer among African Americans and European Americans in PCaP , 2015, PloS one.

[9]  G. Prins,et al.  Differential expression and regulation of vitamin D hydroxylases and inflammatory genes in prostate stroma and epithelium by 1,25-dihydroxyvitamin D in men with prostate cancer and an in vitro model , 2015, The Journal of Steroid Biochemistry and Molecular Biology.

[10]  M. Laakso,et al.  Serum 25-Hydroxyvitamin D: A Predictor of Macrovascular and Microvascular Complications in Patients With Type 2 Diabetes , 2014, Diabetes Care.

[11]  E. Orwoll,et al.  Vitamin D and DBP: The free hormone hypothesis revisited , 2014, The Journal of Steroid Biochemistry and Molecular Biology.

[12]  J. Pike,et al.  Fundamentals of vitamin D hormone-regulated gene expression , 2014, The Journal of Steroid Biochemistry and Molecular Biology.

[13]  H. Y. Chen,et al.  Common vitamin D pathway gene variants reveal contrasting effects on serum vitamin D levels in African Americans and European Americans , 2014, Human Genetics.

[14]  P. Goodman,et al.  Serum 25-Hydroxyvitamin D Concentrations and Risk of Prostate Cancer: Results from the Prostate Cancer Prevention Trial , 2014, Cancer Epidemiology, Biomarkers & Prevention.

[15]  S. Chanock,et al.  Genome-wide association study of circulating vitamin D-binding protein. , 2014, The American journal of clinical nutrition.

[16]  R. Kittles,et al.  Vitamin D Deficiency Predicts Prostate Biopsy Outcomes , 2014, Clinical Cancer Research.

[17]  D. Bikle,et al.  Vitamin D metabolism, mechanism of action, and clinical applications. , 2014, Chemistry & biology.

[18]  Anirban P. Mitra,et al.  Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. , 2013, The Journal of urology.

[19]  Ishir Bhan,et al.  Vitamin D-binding protein and vitamin D status of black Americans and white Americans. , 2013, The New England journal of medicine.

[20]  N. Keating,et al.  Ultraviolet index and racial differences in prostate cancer incidence and mortality , 2013, Cancer.

[21]  M. Rowling,et al.  Vitamin D Transport Proteins Megalin and Disabled-2 Are Expressed in Prostate and Colon Epithelial Cells and Are Induced and Activated by All-Trans-Retinoic Acid , 2013, Nutrition and cancer.

[22]  E. Garrett-Mayer,et al.  Vitamin D3 supplementation, low-risk prostate cancer, and health disparities , 2013, The Journal of Steroid Biochemistry and Molecular Biology.

[23]  Anirban P. Mitra,et al.  Discovery and Validation of a Prostate Cancer Genomic Classifier that Predicts Early Metastasis Following Radical Prostatectomy , 2013, PloS one.

[24]  T. H. van der Kwast,et al.  Randomized clinical trial of vitamin D3 doses on prostatic vitamin D metabolite levels and ki67 labeling in prostate cancer patients. , 2013, The Journal of clinical endocrinology and metabolism.

[25]  Sean R. Davis,et al.  NCBI GEO: archive for functional genomics data sets—update , 2012, Nucleic Acids Res..

[26]  R. Kittles,et al.  Predictors of Serum Vitamin D Levels in African American and European American Men in Chicago , 2012, American journal of men's health.

[27]  M. Hewison.  Vitamin D and immune function: an overview , 2011, Proceedings of the Nutrition Society.

[28]  M. Haussler,et al.  Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)₂vitamin D₃: genomic and non-genomic mechanisms. , 2011, Best practice & research. Clinical endocrinology & metabolism.

[29]  C. Gordon,et al.  Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. , 2011, The Journal of clinical endocrinology and metabolism.

[30]  Rafael A. Irizarry,et al.  A framework for oligonucleotide microarray preprocessing , 2010, Bioinform..

[31]  Scott M. Williams,et al.  Blood Vitamin D Levels in Relation to Genetic Estimation of African Ancestry , 2010, Cancer Epidemiology, Biomarkers & Prevention.

[32]  D. Trump,et al.  The role of vitamin D in cancer prevention and treatment. , 2010, Endocrinology and metabolism clinics of North America.

[33]  L. Nonn,et al.  mRNA and micro-RNA expression analysis in laser-capture microdissected prostate biopsies: valuable tool for risk assessment and prevention trials. , 2010, Experimental and molecular pathology.

[34]  R. Hayes,et al.  Vitamin D-related genes, serum vitamin D concentrations and prostate cancer risk. , 2009, Carcinogenesis.

[35]  Carlos A Camargo,et al.  Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. , 2009, Archives of internal medicine.

[36]  R. Kittles,et al.  Race, Genetic West African Ancestry, and Prostate Cancer Prediction by Prostate-Specific Antigen in Prospectively Screened High-Risk Men , 2009, Cancer Prevention Research.

[37]  M. Haussler,et al.  Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention. , 2008, Nutrition reviews.

[38]  Stefan Pilz,et al.  Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. , 2008, Archives of internal medicine.

[39]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[40]  R. DiPaola,et al.  Vitamin D Inhibits the Formation of Prostatic Intraepithelial Neoplasia in Nkx3.1; Pten Mutant Mice , 2006, Clinical Cancer Research.

[41]  P. Lips.  Vitamin D physiology. , 2006, Progress in biophysics and molecular biology.

[42]  B. Hollis.  Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. , 2005, The Journal of nutrition.

[43]  R. Vieth,et al.  Pilot Study: Potential Role of Vitamin D (Cholecalciferol) in Patients With PSA Relapse After Definitive Therapy , 2005, Nutrition and cancer.

[44]  M. Holick.  Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. , 2004, The American journal of clinical nutrition.

[45]  Benjamin M. Bolstad,et al.  affy - analysis of Affymetrix GeneChip data at the probe level , 2004, Bioinform..

[46]  M. Stephens,et al.  Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. , 2003, Genetics.

[47]  M. Wellner,et al.  Expression profiling confirms the role of endocytic receptor megalin in renal vitamin D3 metabolism. , 2002, Kidney international.

[48]  E. Christensen,et al.  Megalin and cubilin: multifunctional endocytic receptors , 2002, Nature Reviews Molecular Cell Biology.

[49]  J. McNeal,et al.  Reduced 1alpha-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition. , 2001, Cancer research.

[50]  A. Howie,et al.  Extrarenal Expression of 25-Hydroxyvitamin D3-1α-Hydroxylase1 , 2001 .

[51]  H. Pols,et al.  Anti-tumor effects of 1,25-dihydroxyvitamin D3 and vitamin D analogs. , 2000, Current pharmaceutical design.

[52]  T. Chen,et al.  Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[53]  G. Siegal,et al.  1 alpha,25-Dihydroxyvitamin D (calcitriol) inhibits the invasiveness of human prostate cancer cells. , 1997, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[54]  D. Peehl,et al.  Vitamin D and prostate cancer: 1,25 dihydroxyvitamin D3 receptors and actions in human prostate cancer cell lines. , 1993, Endocrinology.

[55]  B. Hollis,et al.  Racial pigmentation and the cutaneous synthesis of vitamin D. , 1991, Archives of dermatology.

[56]  Schwartz Gg,et al.  Is vitamin D deficiency a risk factor for prostate cancer? (Hypothesis). , 1990 .

[57]  C. Mendel.  The free hormone hypothesis: a physiologically based mathematical model. , 1989, Endocrine reviews.

[58]  J. Haddad,et al.  Assessment of the free fraction of 25-hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein. , 1986, The Journal of clinical endocrinology and metabolism.

[59]  R. Anderson,et al.  Photosynthesis of previtamin D3 in human skin and the physiologic consequences. , 1980, Science.

[60]  P. Dhawan,et al.  Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects. , 2016, Physiological reviews.

[61]  A. Jemal,et al.  Cancer statistics, 2016 , 2016, CA: a cancer journal for clinicians.

[62]  K. Saika.  Incidence and Mortality of Lung Cancer , 2015 .

[63]  P M Stewart,et al.  Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. , 2001, The Journal of clinical endocrinology and metabolism.

[64]  B. Hulka,et al.  Is vitamin D deficiency a risk factor for prostate cancer? (Hypothesis). , 1990, Anticancer research.

[65]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.